Memory-altering drugs may rewrite your past
03 December 2005
NewScientist.com news service
Gaia Vince
"REMEMBER September 11, 2001, when you first heard the news about the World Trade Center attacks? Remember where you were when you saw those images? Now, think back to September 10. It was only one day before. Remember that day? Anything at all?"

Roger Pitman, a psychiatrist at Harvard Medical School, is asking an updated version of the well-known Kennedy assassination question to make a telling point. While few of us can remember an ordinary day four years ago, for many of us the events of 11 September are indelibly etched on our minds. Pitman is demonstrating that the brain handles memories of traumatic or emotionally charged events in a different way to neutral ones - they are seared into the brain more deeply, and remembered for longer.

There's a good reason why this might be. From an evolutionary perspective, it pays to attach special importance to emotionally charged events so you can respond better next time. But there is sometimes a price to be paid. Up to a third of those who experience a traumatic event first-hand go on to develop post-traumatic stress disorder (PTSD).

Whether triggered by a terrorist attack or a natural disaster, a violent crime or a car crash, people with PTSD can be plagued by terrifying flashbacks and suffer crippling fear in reaction to reminders of their trauma. PTSD can be so debilitating that it prevents people from leading a normal life, and can last a lifetime.

All the PTSD treatments available have their drawbacks. But in the past couple of years a novel approach has created a stir in the field, and beyond. Significant advances in our understanding of the way the brain forms and retrieves memories are leading neuroscientists to test drugs that specifically block or erase problem memories at the molecular level. For chronic PTSD sufferers it's a potential lifeline that few dared dream of, with early results suggesting a much better success rate than existing treatments. "It represents one of the most exciting discoveries in the history of physiological psychology," says Pitman.

Wipe away your guilt

Not everybody is entirely comfortable with the notion of developing drugs to alter unwanted memories. Memories make up a big part of what it means to be human; what would it mean to selectively excise them? Few would be happy with the idea of giving soldiers a drug that made the memory of killing someone no more troubling than that of cleaning their boots. And, if it were possible to home in on fearful memories in this way, what about other kinds of emotional memory? It might even be possible to develop drugs that cosmetically adjust our memories, removing traces of shame, guilt or grief.

PTSD may seem a very modern illness, but descriptions of the condition date back to ancient Egypt. More recently, soldiers from the first world war were diagnosed with "shell shock", but it wasn't until 1980 that the American Psychiatric Association added PTSD to its list of recognised mental disorders.

There are several treatments available for PTSD (see "Treating post-traumatic stress disorder"), but success rates vary widely. More than half of patients experience some improvement but few achieve a complete cure and for a large proportion nothing works. That's why memory alteration is causing such a stir. But how is it possible to target the fearful memories of PTSD without erasing other memories too? The answer lies in the special way that the brain processes emotionally charged experiences.

Stimuli from your sense organs are continuously entering your brain and converging on the thalamus, a clearing house for the senses. From there, the information is quickly dispatched along an express route to an almond-shaped region of the forebrain called the amygdala for a crude assessment of the "emotional quality" of the stimuli. If the amygdala recognises a potentially threatening component - such as the screeching brakes of a large vehicle or a curved shape on the ground that could be a snake - it triggers the body's stress responses: a typical "fight or flight" rush of adrenalin and noradrenalin.

"It's a quick and dirty response," says Pitman. "The amygdala triggers a rapid fear response to allow the body to take evasive action." Simultaneously to the "quick and dirty" response, other paths take signals from the thalamus to higher areas of the brain for more considered analysis of whether the stimuli represent a threat. "If, for example, the curve turns out to be a piece of hosepipe in the grass, then the prefrontal cortex reins in the amygdala response," Pitman says.

But if the stimuli turn out to represent a genuine threat, adrenalin and noradrenalin trigger a cascade of reactions in the amygdala, which then instructs the hippocampus - the brain's memory centre - to process the memory of those fear-inducing stimuli in a special way, imprinting them deeper than usual. "This stress-induced memory boost is a mechanism that evolved for survival," says Chris Brewin, a PTSD specialist at the Traumatic Stress Clinic in London. "Something very threatening needs to be remembered, so in the future, you're primed for action immediately."

Over the next few months, any stimulus similar to those experienced in the original trauma - even harmless ones - can trigger an exaggerated stress response in the amygdala. After a while most people learn that these stimuli are not a threat, and their brains make new pathways that override the old one, though they don't erase it. This process is called extinction. However, in some people - up to 30 per cent of those who directly experience a bombing, for example - the extinction mechanism doesn't work and the prefrontal cortex consistently fails to reign in the amygdala. The result is PTSD.

Recently, Pitman and other researchers have been looking at ways of intervening directly in memory formation as a way to combat PTSD. The idea originated in the 1990s when researchers experimenting on rats discovered that the enhancing effect of fear on memory formation could be reduced by beta-blockers, a type of drug widely used to control blood pressure. Beta-blockers bind to receptors on the cell surface that normally bind adrenalin and noradrenalin, and so counteract their biological effects - including the effect on memory formation.

In 2001 Pitman put the idea to the test in humans. He set up an alert system with Massachusetts General Hospital's emergency room so that when a person was brought in after a traumatic incident, such as a car crash or a rape, they were given the option of taking part in his experiment. Those who agreed were given a tablet of either the beta-blocker propranolol or a placebo.

Pitman later asked the subjects to describe the traumatic event they had experienced and recorded their stories on to audio tape. Three months later he asked them to picture the event while listening to the recording, while he monitored their heart rate and other physiological reactions. In the placebo group, 43 per cent showed symptoms of stress such as increased heart rate and sweating. In stark contrast, none of the people who had received propranolol showed excess stress (Biological Psychiatry, vol 51, p 189).

Though it was just a small study - only 22 people completed it - the research generated much interest. "It was the first time it had been possible to prevent PTSD from occurring by using a drug," says Pitman.

It's never too late

And beta-blockers may be able to do more than just prevent PTSD from occurring. They may be able to treat the condition after it has developed, perhaps even decades later. In the past few years neuroscientists have discovered that memories are much more fluid than was once thought (New Scientist, 3 May 2003, p 26). Researchers at McGill University in Montreal, Canada, working with rats that had been conditioned to fear a harmless sound, discovered that each time the rats heard the sound, their fear memory became labile again for a short time and could be altered. This suggested that memories which appeared to be hard-wired long ago could be made pliable if they were recalled under emotive conditions. "This provides an important second window of opportunity," says Pitman.

This year Pitman has been carrying out a trial involving more than 20 people with long-standing PTSD who were given either propanolol or a placebo. Again, he recorded descriptions of each person's trigger event, and played back the recording three months later while measuring their physiological responses. He plans to announce the results in the new year.

Another team of researchers that includes Margaret Altemus of Cornell University in New York and Joseph LeDoux of New York University also plan to investigate propranolol treatment by allowing people with PTSD to self-administer the drug during a flashback, when the memory also becomes labile.

These trials focus on people who have PTSD or are at risk of developing it, but, Pitman says, any strongly emotional memory - from winning the lottery to the death of a loved one - could be reduced through the same process. "Emotional memories are excessively imprinted, and propranolol is able to reduce them to the level of an ordinary non-emotionally charged memory," he says.

What that means, of course, is that if a patient happened to recall a different emotionally charged memory - a valued one, perhaps - during treatment for PTSD, that memory might also fade into the background. Pitman admits this is a genuine risk though he hasn't investigated it yet.

tryptych

01-12-2005, 03:25 PM

Continued....

Meanwhile, other researchers have begun investigating the connection between cortisol, a hormone involved in the response to stress, and PTSD. The link between cortisol and PTSD was first noticed by Gustav Schelling, an intensive-care doctor at the Ludwig-Maximilian University Hospital in Munich, Germany. He treats a lot of people with septic shock, a potentially fatal condition caused by an overreaction of the immune system. These people often experience severe stress and pain, and it is not uncommon for them to go on to develop PTSD.

One of the treatments for septic shock is hydrocortisone, a synthetic version of cortisol and a potent immunosuppressor. Schelling noticed that PTSD seemed to be less common in those who had received hydrocortisone treatment. So he reanalysed the data from a small placebo-controlled trial his hospital had carried out into the effectiveness of hydrocortisone in treating septic shock. He found that seven of the 11 people (64 per cent) in the placebo group developed PTSD, compared with only nine out of 20 (45 per cent) of the hydrocortisone group.

The role of cortisol in PTSD is not fully understood, but the hormone is known to inhibit memory retrieval, possibly by diverting blood glucose away from the hippocampus and towards the muscles as part of the stress response. It's something actors are all too familiar with: when stage fright kicks in, their memory goes blank.

People with PTSD have been shown to have much lower baseline levels of cortisol in their brains. As a result, some researchers think, their emotional memories may be easier to retrieve, resulting in vivid flashbacks, or intrusions. Schelling thinks that disrupting memory retrieval during stressful events such as septic shock somehow protects against the development of PTSD.

Hydrocortisone is also being investigated as a treatment for established PTSD. Psychiatrist Dominique de Quervain of the University of Zurich in Switzerland gave three people with chronic PTSD a low daily dose of cortisol for a month and asked them to rate any change in the severity of their symptoms. All three reported that their symptoms were around a third less severe, with no side effects or alterations of other memories (The American Journal of Psychiatry, vol 161, p 1488).

Richard Bryant, a psychiatrist specialising in PTSD at the University of New South Wales in Sydney, Australia, is trying a different approach. He is using D-cycloserine (DCS), an antibiotic usually prescribed for TB. He chose the drug because one of its side effects is to promote the release of a brain chemical called glutamate, which is known to enhance learning. For this reason, the drug is sometimes administered to Alzheimer's patients as a memory booster. The idea is to use DCS alongside cognitive behavioural therapy to try to enhance the normal memory extinction process and prevent the development of PTSD in people who have recently witnessed traumatic events. The study is not yet completed, but the results so far appear impressive, he says.

It is early days for all these approaches, but it already seems that memory-altering drugs are a promising approach to PTSD treatment, and may get even better once drugs are specifically designed to alter memory rather than just utilising the side effects of existing ones. "This is probably the first serious convergence of psychological therapy and neuroscience, so it's quite intriguing and very exciting," says Bryant.

But our increasing understanding of memory and ways in which it can be manipulated might have profound effects beyond PTSD. The ability to block intrusive or traumatic memories may end some people's nightmares. But what of memories that are merely undesirable rather than pathological? Should humiliating, embarrassing or distressing episodes prompt us to swallow a liquor of forgetfulness? "People tend to think about memory-altering drugs as science fiction," says Richard Glen Boire from the Center for Cognitive Liberty and Ethics in Davis, California. "Not true. These drugs will be available within five to 10 years and they will alter our lives entirely. In modulating a person's memories, we are talking about nothing less than altering the central part of what it means to be a human being."

Boire nevertheless believes that individuals ought to have the right to manage their own memories. "I would not say that a Holocaust survivor should be prevented from wiping painful memories, just so that society can 'benefit' from their experience," he says. But he points out potential pitfalls. What if criminals took a memory-wiping drug so they could not recall their crimes and believed they never committed them? Should people be allowed to rewrite the memory of others?

Other experts are less comfortable with the notion. "I certainly wouldn't want to rewrite the past," says Eric Kandel, a Nobel prize-winning memory researcher at Columbia University in New York. "A person who has undergone something they feel guilty about is troubled by their memory for a reason. The nightmares make them a better person, because they realise the implications of their actions - it feels bad to hurt other people. I believe such drugs will make us worse as people."

"What is no longer in doubt is that the technology to carry out this type of memory erasure will exist," Kandel says. "Now we have to decide if it is ethically acceptable."

Treating post-traumatic stress disorder

COGNITIVE BEHAVIOURAL THERAPY

A form of psychotherapy which attempts to teach people to recognise and change upsetting thoughts. Patients are encouraged to discuss the frightening event with their therapist with the goal of learning to respond to the memories more normally. Recommended by the World Health Organization.

EYE MOVEMENT DESENSITISATION AND REPROCESSING

A controversial therapy, developed in the US in 1989. This involves getting the patient to think about the traumatic event while they watch the movements of an object, such as the therapist's finger or a pen. It is unclear how this treatment works, or how successful it is.

DEBRIEFING

Perhaps more controversial still. Debriefing is a one-off session with a therapist, often in a group setting, a few days after the traumatic event. This has been widely used but recent studies have suggested it can actually raise the risk of developing PTSD. The WHO has recently come down heavily against the technique.

DRUGS

Anti-anxiety drugs such as paroxetine, a member of the Prozac class, can help reduce some symptoms, such as panic or depression, but are less good against others, such as intrusive memories and nightmares.

I'm amazed that people seriously would consider such playing with such delicate things as memory so directly, when there are some pretty good tools available already, such as the combination of CBT/hypnosis and the positive results coming in for MDMA assited therapy for PTSD.

DJ PIMP

08-12-2005, 02:42 AM

Blah. What are we going to do with all our free-time if we don't have neuroses to obsess over?